α2 receptors include neuronal α2 receptors and non-neuronal α2 receptors. The neuronal α2 receptors are classified into presynaptic α2 receptors and postsynaptic α2 receptors. The former is distributed particularly in peripheral and central noradrenergic nerve terminals and inhibits the release of noradrenalin. Besides, it is also distributed in, for example, cholinergic and serotoninergic nerve terminals and inhibits the release of various types of neurotransmitters. The latter is distributed in, for example, the central nervous system, the sympathetic ganglion, and noradrenergic neuronal dendrites and involved in physiological functions such as hypotensive/bradycardic effects, hyperpolarizing effects, and inhibitory effects on neuronal excitation, respectively. On the other hand, the non-neuronal α2 receptors are distributed in, for example, blood platelets, adipocytes, pancreatic islets of Langerhans, and vascular endothelial cells and involved in physiological functions such as antiplatelet effects, inhibitory effects on lipid degradation, inhibitory effects on insulin secretion, and NO-releasing effects, respectively (Non-Patent Document 1).
Yohimbine or the like is known as an α2 receptor blocking drug known in the art. Yohimbine is indole-based alkaloid contained in the bark of Pausinystalia yohimbe (a tree of the family Rubiaceae) or in plants of the genus Rauwolfia and is a drug used as an aphrodisiac. Patients with impotence are now sharply increasing due to drugs, geriatric diseases, malignant tumor operations, social environments, mental stresses, and the like. However, a therapy thereof has not been established because the cause of the disease is complicated.
A drug having an α2-receptor antagonistic effect has potential use in many applications such as an aphrodisiac and anti-diabetic drug.
However, yohimbine, which is a pentacyclic condensed heterocyclic compound, is difficult to synthesize due to its complicated structure. Moreover, its complicated structure is a possible cause of side effects.
On the other hand, melatonin (N-acetyl-5-methoxyindole-3-ethaneamine), an indole derivative, represented by the following formula:
wherein R1 represents a hydrogen atom, R2 represents a methyl group, R3, R4, R6, R7, and R8 represent a hydrogen atom, R5 represents a methoxy group, n represents 2, a represents 0, and b represents 1, has been reported to act in an inhibitory manner on both osteoblasts and osteoclasts (Non-Patent Document 2) and to be effective for female androgenic alopecia and diffuse alopecia (Patent Document 1). Patent Document 2 has disclosed that an indole derivative analogous to melatonin has an intraocular pressure-reducing effect. Alternatively, Patent Document 3 and Non-Patent Document 3 have described a brominated derivative of melatonin, and Non-Patent Document 4 has described various types of 3-substituted indole derivatives.
However, there has been no report that melatonin and indole derivatives analogous to melatonin have an α2-receptor antagonistic effect.
Patent Document 1: JP 2004-500353A
Patent Document 2: U.S. Pat. No. 6,730,707
Patent Document 3: JP 9-511514A
Non-Patent Document 1: I. Muramatsu, Journal of the Japan Pharmaceutical Association, 48 (11), 1987 (1996)
Non-Patent Document 2: N. Suzuki, and A. Hattori, J. Pineal Res., Vol. 33, pp. 253-258 (2002)
Non-Patent Document 3: M. Somei, Y. Fukui, M. Hasegawa, N. Oshikiri, and T. Hayashi, Heterocycles, Vol. 53, pp. 1725-1736 (2000)
Non-Patent Document 4: M. Somei, Recent Advances in the Chemistry of 1-hydroxyindoles, 1-Hydroxytryptophans, and 1-Hydroxytryptamines, Advances in Heterocyclic Chemistry, Vol. 82, ed. by A. R. Katritzky, Elsevier Science (USA), 2002, pp. 101-155